The present invention relates to a method of treating hematologic diseases in a warm-blooded living being.
Hematologic diseases, including immunodeficiency, anemia, result from a deficiency or defect in the capacity of the bone marrow cells to support hematopoiesis or in the ability of the living being to regulate production of blood cells. Means to regulate, support or enhance repopulation of bone marrow cells have been of interest for several decades, but satisfactory methods of regulation are still unavailable. Early research on hematopoietic stimulation (or repopulation) was related to efforts to rescue experimental animals from radiation-induced bone marrow suppression. Recent evidence that emphasizes the persistence of need for methods to regulate blood cell production was the futile attempt to rescue hematopoietically depressed victims of the Chernobyl nuclear power plant accident. It would be revolutionary to be able to regulate production of blood cells by the use of therapeutic agents. Such agents could have potential in treatment of patients with a broad range of diseases such as acquired immunodeficiency syndrome (AIDS) and AIDS related complex (ARC), including patients suffering from anemia, granulocytopenia or from immunodeficiency, (e.g., congenital, acquired or induced for organ transplantation). It must be emphasized that many years of diligent effort will be required to realize such a potential.
Consequently, there exists a long standing need for agents that have a potential to regulate or stimulate the production of blood cells, in particular of leukocytes, but also of lymphocytes, erythrocytes and blood platelets. Such agents would be therapeutic because many types of patients are hematologically suppressed and prone to infection. In fact many patients taking anti-cancer drugs suffer hematopoietic (and immunologic) suppression and may succumb to infectious diseases rather than cancer. Agents having a potential to regulate or stimulate blood cell production are considered therapeutically significant, not only in human medicine but also in veterinary science.
In order to asses hematopoietic effects the inventor has conducted studies on the influence of numerous agents on hematopoietic stem cells in an animal model system. As a result of such studies, it has now been found that certain amide compounds regulate or stimulate production of hematopoietic cells and, therefore, may be used for treating hematologic diseases.
Consequently the present invention relates to a method of treating hematologic diseases in warm-blooded living beings, comprising administering to the living being in an amount effective for regulating or stimulating hematopoiesis a composition comprising as the active substance at least one compound of the general formula ##STR2## wherein R.sub.5 represents (a) 1-3 substituents selected from the group consisting of halogen, C.sub.1 -C.sub.6 alkyl, trifluoromethyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, hydroxy, C.sub.2 -C.sub.6 alkanoyloxy, amino, N, N-di(CC.sub.1 -C.sub.4) alkylamino and piperidyl; or (b) five fluorine atoms;
X is an oxygen atom or a sulphur atom; PA0 Y is an oxygen atom or a sulphur atom; PA0 R.sub.6 represents 1-3 substituents selected from the group consisting of halogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkoxy, cyclohexyloxy, adamantyloxy, hydroxy, amino and N-C.sub.2 -C.sub.5 alkanoylamino.
The compounds to be used as active substances in the above compositions are partly known compounds, e.g. from European patent applications 25363, 107214, 164694, 166615, 169484, 178572, 192235 and 226104. In these patent publications an antitumor activity is demonstrated for the compounds disclosed, making them potentially valuable for the chemotherapeutic treatment of malignant tumors. It is generally known, however, that chemotherapeutic drug usually have a suppressive effect on blood cell production; see e.g. in this connection a recent article of Kulik and coworkers (Chem Abstr. 106, 1987, 188563). Therefore it is surprising, that the above-defined compounds show stimulating effects on hematopoietic stem cells and consequently offer an interesting potential for regulating or stimulating blood cell production.
In particular 1-(2,6-difluorobenzoyl)-3-(4-chlorophenyl)urea (1) and 1-(2-N,N-dimethylamino-6-fluorobenzoyl)-3-(4-chlorophenyl)urea (2) have proven to be highly suitable for achieving the intended effect.
Compounds which can be used as active substances for treating hematologic diseases in warm-blooded living beings are tabulated below: Tables E
TABLE E ______________________________________ ##STR3## comp. no. R.sub.5 R.sub.6 X Y ______________________________________ 1 2,6-F.sub.2 4-Cl O O 2 2-F, 6-N(CH.sub.3).sub.2 4-Cl O O 3 2,6-F.sub.2 4-CF.sub.3 O O 4 2-F, 6-(1-piperidyl) 4-CF.sub.3 O O 5 2-F, 6-N(CH.sub.3).sub.2 4-OCF.sub.2.CHF.sub.2 O O 6 2-Cl, 6-OH 4-Cl O O 7 2,3,4-(OH).sub.3 4-Cl O O 8 2,6-F.sub.2 4-O-(1-adamantyl) O O 9 2-OCH.sub.3, 6-N(CH.sub.3).sub.2 4-Cl O O 10 2-OCH.sub.3, 6-N(CH.sub.3).sub.2 3-CF.sub.3 O O 11 2-Cl, 6-SCH.sub.3 3-CF.sub.3, 4-OH O O 12 2-OCH.sub.3, 6-N(CH.sub.3).sub.2 4-NH.CO.CH.sub.3 O O 13 2,6-(SCH.sub.3).sub.2 4-Cl O O 15 2-OCH.sub.3, 6-N(CH.sub.3).sub.2 4-OCF.sub.3 O O 16 4-CF.sub.3 4-Cl O O 17 2,6-F.sub.2 3-Cl, 4-OH O O 18 2,3,4,5,6-F.sub.5 3-F, 4-Cl O O 19 3,5-(OH).sub.2 4-Cl O O 20 2,6-F.sub.2 3,4,5-(OH).sub.3 O O 21 2,4-(OH).sub.2 4-l O O 22 3,4,5-(OH).sub.3 4-Cl O O 23 4-NH.sub.2 2-NH.sub.2 O O 24 2-Cl, 6-OH 4-CF.sub.3 O O 25 2-F, 6-OH 4-Cl O O 26 2-NH.sub.2 4-Cl O O 27 2-F, 6-N(CH.sub.3)2 4-OCH.sub.3 O O 28 2-SCH.sub.3 4-Cl O O 29 2,3-(OH).sub.2 4-Cl O O 30 3,4-(OH).sub.2 3,4-(OH).sub.2 O O 31 4-Cl 3,5-(t.butyl).sub.2, 4-OH O O 32 2,6-F.sub.2 3,5-Cl.sub.2, 4-OCH.sub.2 CF.sub.3 O O 33 2-F 4-Cl O O 34 2,6-F.sub.2 4-F O O 35 H 4-Cl O O 36 2,6-F.sub.2 4-OCF.sub.2 CHFCl O O 37 4-O.COCH.sub.3 2-OH, 4-Cl O O 38 2-OCH.sub.3, 4-N(CH.sub.3).sub.2 3-CF.sub.3, 4-OH O O 39 2-Cl, 4-NH.sub.2 3,4-Cl.sub.2 O O 40 2-OCH.sub.3, 6-N(CH.sub.3).sub.3 3-Cl, 4-OH O O 42 2,6-(OH).sub.2 4-Cl O O 43 2,6-F.sub.2 3-CF.sub.3 O O 44 2-SCH.sub.3 4-Cl O S 45 2-OH 4-Cl O S 46 3-Cl 2-NH.sub.2 O S 47 2,6-F.sub.2 4-Cl O S 48 2-OCH.sub.3 4-C.sub.2 H.sub.5 O S 49 2-OH 4-Cl S S 78 2,6-(CH.sub.3).sub.2 4-Cl O S 79 2,6-F.sub.2 4-O-cyclohexyl O O 80 2,6-F.sub.2 2,3,4,5,6-F.sub.5 O O ______________________________________
Part of the above active compounds is new. The new compounds can be prepared in a manner known per se for related compounds, The new compounds of the present invention can be prepared by reacting a substituted amino compound of the general formula ##STR4## wherein R.sub.6 has the above meaning, with an iso(thio)cyanato compound of the general formula ##STR5## wherein R.sub.5, X and Y have the above meanings.
The new compounds can also be prepared by reacting a (thio)amide of the general formula ##STR6## wherein R.sub.5 and X have the above meanings, with an iso(thio)cyanate of the general formula ##STR7## wherein R.sub.6 and Y also have the above meanings.
The compounds obtained may be modified by an after-treatment to convert reactive side-chains like hydroxy, amino, etc. into functional derivatives such as alkoxy, N-alkylamino, N-acylamino, etc., and vice versa, to convert functional derivatives into the desired hydroxy, etc. substituted compounds.
The preparation of the new compounds is illustrated in the examples.
The present invention also relates to a pharmaceutical composition to be used for the method of treating hematologic diseases in warm-blooded living beings, comprising in addition to a pharmaceutically acceptable carrier and, if desired, at least one pharmaceutically acceptable adjuvant, as the active substance at least one compound as defined above in an amount effective for treating hematologic diseases. Such a composition may differ substantially from an antitumorous composition. Antitumorous compositions are usually administered repeatedly and therefore are given in relatively greater amounts, i.e. in maximally tolerated doses; such known compositions are generally administered intravenously by infusion, though oral administration is not excluded. The compositions of the present invention, however, are preferably in a form suitable for oral or rectal administration, e.g., in the form of tablets, pills, capsules, suppositories, etc., but may also be in a form suitable for intravenous or subcutaneous administration. In the compositions of the present invention the active substance is incorporated in a considerably lower dosage than for a chemotherapeutic substance.
The present invention further relates to a method of conventionally preparing a composition for treating hematologic diseases, that is, by incorporating the active substance in an amount effective for treating hematologic diseases into a pharmaceutically acceptable carrier, to which, if desired, at least one pharmaceutically acceptable adjuvant is added.
The hematopoietic stimulating activity of the compounds was determined in vivo, using animal model systems, and in vitro, using a culture of hematopoietic colonies.